ABSTRACT Dysfunction and/or degeneration of the enteric nervous system (ENS) can cause gastrointestinal tract dysmotility. One particularly severe and clinically challenging dysmotility disorder in humans is chronic intestinal pseudo-obstruction (CIPO). The most effective current therapies for CIPO are parenteral nutrition and small bowel transplantation. New animal models to develop and test therapeutic options for CIPO are a substantial unmet need in this area. To this end, we found that mice infected with RNA viruses of the Flavivirus genus including West Nile (WNV) demonstrate features of CIPO that may help reveal new modes of treatment. WNV infects enteric neurons in the submucosal and myenteric plexus of the GI tract of mice, resulting in T cell infiltration, injury and cell death of neurons, and decreased bowel motility. The diminished bowel motility occurs in the absence of any gross anatomic or mechanical obstructive defects. In the chronic phase, mice clear virus infection but still have sustained GI dysmotility that resolves slowly over a few months. Remarkably, a relapse of GI dysmotility can be triggered in the convalescent phase after WNV-infected animals are exposed to unrelated inflammatory stimuli. To explain the relapsing/remitting nature of this disease course, we propose a model whereby structural and function defects in the ENS in response to WNV infection and the resultant immune response affect an enteric neuroendocrine-immune (NEI) circuit that, along with the microbiota, becomes chronically dysregulated. In this proposal, we will test novel approaches to correct that dysregulated NEI circuit by modulating: (i) CD8+ T cell responses that induce acute injury of enteric neurons following WNV infection; (ii) the microbiota, which becomes dysregulated following WNV infection and can transfer the dysmotility phenotype to uninfected mice and (iii) neuroendocrine hormones, specifically the 5-HT serotonergic system, which appears diminished in the WNV model. Our goal is to use this mouse model to dissect the underlying regulatory mechanisms of the NEI circuit, elucidate the interplay between the various components of the NEI circuit and the microbiota, and understand how it malfunctions in response to viral infection. Our group will define mechanistically how perturbation of the enteric NEI circuit following WNV infection results in acute, chronic and relapsing GI dysmotility. This information may facilitate the development of agents that prevent damage to or restore the function of the enteric NEI circuit and the microbiota following systemic neurotropic virus infection, which could form the basis of therapies for CIPO and related bowel motility disorders.